Current Medicinal Chemistry - Volume 28, Issue 27, 2021

The COVID-19 (here specifically called Worldwide Acute Respiratory Syndrome, WARS) pandemic is surging worldwide. Unfortunately, no specific drug meets the urgent need to fight this pandemic, leading to thousands of deaths. The theory of host-directed therapies (HDTs) is viewed as the ideal means to rephrase the treatment of infectious diseases. However, related drugs based on this theory have not been identified. Previously, we realized that caffeine is the ligand of type 2 taste receptors (TAS2Rs), which play a critical role in host defense. Here, we gathered data on caffeine acting as an immunomodulator. Unexpectedly, we found that caffeine can fight WARS by acting on multiple organs, which may prevent the virus from entering the cell, stimulate the phagocytosis of macrophages, enhance breathing, and inhibit the cytokine storm. Thus, the immunoprotective effects of caffeine can improve the therapeutic outcomes in patients infected with coronavirus. Collectively, we report that caffeine, an FDA-approved, highly safe, inexpensive, and widely available drug, could be an excellent HDT for battling WARS.

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, fungi, parasites and viruses. Such diseases mostly develop in tropical and sub-tropical climates and represent major health challenges. The pathogens of these diseases are able to multiply in human hosts, warranting their continual survival. Prevention of these diseases is becoming extremely difficult due to the absence of effective vaccines and their treatment, less effective due to the emergence of resistance by their causative pathogens to existing drugs. Several currently available drugs employ oxidative stress, resulting from the generation of reactive oxygen nitrogen species (RONS), as the mechanism for exerting their pharmacological actions. RONS inhibit endogenous antioxidant enzymes, which ultimately eradicate the microbiota. Curcumin, a redox-active natural product, for centuries, has been used in Asian traditional medicine for the treatment of various diseases. It is known for possessing multiple biological and pharmacological activities. Curcumin has been investigated extensively over the years for its anti-inflammatory, anticancer, antiparasitic, antiviral and antibacterial activities, and no toxicity is associated with the compound. Despite its potency and good safety profile, curcumin is still in clinical trials for the treatment of diseases, such as tuberculosis, acquired immunodeficiency syndrome (AIDS), Crohn’s disease, colorectal cancer, and multiple myeloma, among many others, as it is yet to be qualified as a therapeutic agent. This review summarizes events over the last decade, especially regarding the discovery of curcumin, an update of its synthesis, its pathogen specific mechanisms of action, and the pharmacological effects of its derivatives, combinations and formulations as potential antibacterial, antifungal, antiparasitic and antiviral agents for the treatment of various infectious diseases.

Background: Natural products are useful agents for the discovery of new lead- compounds and effective drugs to combat coronaviruses (CoV). Objective: The present work provides an overview of natural substances, plant extracts, and essential oils as potential anti-SARS-CoV agents. In addition, this work evaluates their drug-like properties which are essential in the selection of compounds in order to accelerate the drug development process. Methods: The search was carried out using PubMed, ScienceDirect and SciFinder. Articles addressing plant-based natural products as potential SARS-CoV or SARS-CoV-2 agents within the last seventeen years were analyzed and selected. The descriptors for Chemometrics analysis were obtained in alvaDesc and the principal component analysis (PCA) was carried out in SIMCA version 13.0. Results: Based on in vitro assays and computational analyses, this review covers twentynine medicinal plant species and more than 300 isolated substances as potential anti-coronavirus agents. Among them, flavonoids and terpenes are the most promising compound classes. In silico analyses of drug-like properties corroborate these findings and indicate promising candidates for in vitro and in vivo studies to validate their activity. Conclusion: This paper highlights the role of ethnopharmacology in drug discovery and suggests the use of integrative (in silico/ in vitro) and chemocentric approaches to strengthen current studies and guide future research in the field of antiviral agents.

Background: Cancer, along with cardiovascular diseases, is globally defined as the leading cause of death. Importantly, some risk factors are common to these diseases. The process of angiogenesis and platelet aggregation is observed in cancer development and progression. In recent years, studies have been conducted on nanodrugs for these diseases that have provided important information on the biological and physicochemical properties of nanoparticles. Their attractive features are that they are made of biocompatible, well-characterized, and easily functionalized materials. Unlike conventional drug delivery, sustained and controlled drug release can be obtained by using nanomaterials. Methods: In this article, we review the latest research to provide comprehensive information on nanoparticle-based drugs for the treatment of cancer, cardiovascular disease associated with abnormal haemostasis, and the inhibition of tumor-associated angiogenesis. Results: The results of the analysis of data based on drugs with nanoparticles confirm their improved pharmaceutical and biological properties, which give promising antiplatelet, anticoagulant, and antiangiogenic effects. Moreover, the review included in vitro, in vivo research and presented nanodrugs with chemotherapeutics approved by Food and Drug Administration. Conclusion: By the optimization of nanoparticle size and surface properties, nanotechnology is able to deliver drugs with enhanced bioavailability in treatment of cardiovascular disease, cancer and inhibition of cancer-related angiogenesis. Thus, nanotechnology can improve the therapeutic efficacy of the drug, but there is a need for a better understanding of the nanodrugs interaction in the human body because this is a key factor in the success of potential nanotherapeutics.

Considering that cancer continues to be an important cause of death worldwide, several conventional anticancer treatments are widely used. However, most of them display low selectivity against malignant cells and induce many adverse side effects. Among these, the use of therapies based on 5-Fluorouracil (5-FU) has been one of the most efficient, with a broad-spectrum. Due to these circumstances, various modifications of 5-FU have been developed to improve drug delivery and reduce side effects. Among the optimization strategies, modifications of 5-FU at N1 or N3 position are made, usually including the incorporation of pharmacologically active compounds with anticancer activity (called hybrid molecule) and functionalization with other groups of compounds (called conjugates). Several studies have been conducted in the search for new alternative therapies against cancer. Many of them have evidenced that hybrid compounds exhibit good anticancer activity, which has emerged as a promising strategy in this field of drug discovery and development. Furthermore, the binding of 5-FU to amino acids, peptides, phospholipids, polymers, among others, improves metabolic stability and absorption. This review highlights the potential of hybrids and derivatives based on 5-FU as a scaffold for the development of antitumor agents. Besides, it also presents a detailed description of the different strategies employed to design and synthesized these compounds, together with their biological activities and structure-activity relationship (SAR) analysis.

Background: Alport syndrome (AS) is a disease caused by mutations in COL4A3, COL4A4 or COL4A5, the genes that encode distinct chains of type IV collagen. The vast majority of cases present as an inherited disorder, although de novo mutations are present in around 10% of the cases. Methods: This non-systematic review summarizes recent evidence on AS. We discuss the genetic and pathophysiology of AS, clinical manifestations, histopathology, diagnostic protocols, conventional treatment and prognostic markers of the disease. In addition, we summarize experimental findings with novel therapeutic perspectives for AS. Results: The deficient synthesis of collagen heterotrimers throughout the organism leads to impaired basement membranes (BM) in several organs. As a result, the disease manifests in a wide range of conditions, particularly renal, ocular and auricular alterations. Moreover, leiomyomatosis and vascular abnormalities may also be present as atypical presentations. In this framework, diagnosis can be performed based on clinical evaluation, skin or renal biopsy and genetic screening, the latter being the gold standard. There are no formally approved treatments for AS, even though therapeutic options have been described to delay disease progression and increase life expectancy. Novel therapeutic targets under pre-clinical investigation included paricalcitol, sodium-glucose co-transporter- 2 inhibitors, bardoxolone methyl, anti-microRNA-21 oligonucleotides, recombinant human pentraxin-2, lysyl oxidase-like-2 blockers, hydroxypropyl-b-cyclodextrin, sodium 4-phenylbutyrate and stem cell therapy. Conclusion: AS is still a greatly under and misdiagnosed disorder. The pathophysiology is still not fully understood and genetics of the disease also have some gaps. Up to know, there is no specific and effective treatment for AS. Further studies are necessary to establish novel and effective therapeutic protocols.

Background: Lipids are essential components of cells that participate in metabolic and endocrine regulation and reproductive functions. The main organs where lipid regulation takes place are the liver and adipose tissue. Besides, when each tissue- specific action cannot be exerted, it could lead to several endocrine-metabolic disorders closely related to PCOS, such as non-alcoholic fatty liver disease (NAFLD) and obesity. Objective: This work aims to discuss the impact of lipid alterations on metabolic and reproductive health. Therefore, this review focus on the importance of carrying out an integrated study of the molecular pathways affected in PCOS for developing target therapies. Results: Lipids play a major role in PCOS pathogenesis. In this regard, failures in lipid regulation, synthesis, and/or homeostasis contribute to metabolic and reproductive abnormalities, such as those seen in PCOS. Several lipid pathways and regulators are altered in this pathology, leading to dysfunctions that worsen reproductive functions. Therefore, there are several treatments to manage dyslipidemias. Non-pharmacological therapies are considered a first-line treatment being the pharmacological treatments a second-line option. Conclusion: The best treatment to improve the lipid profile is lifestyle intervention, a combination of hypocaloric diet and exercise. Regarding pharmacological therapies, a combination of fibrate and statins would be the most recommended drugs. Still, in PCOS women, treatment with metformin or TZDs not only modulates the lipid metabolism, but also improves ovulation. In addition, metformin with lifestyle interventions has positive effects on the metabolic and reproductive features of PCOS patients.

Background: An association between migraine and Major Depression (MD) has been revealed in a number of clinical studies. Both diseases have affected a large global population. More understanding of the comorbidity mechanism of these two diseases can shed light on developing new therapies for their treatment. Methods: To the best of our knowledge, there have not been any researches in the literature based on microRNA (miRNA) biomarkers to investigate the relationship between MD and migraine. In this study, we have discussed the association between these two diseases based on their miRNA biomarkers. In addition to miRNA biomarkers, we have also demonstrated epidemiological evidence for their association based on Taiwan Biobank (TWB) data. Results: Among the 12 migraine miRNA biomarkers, 11 are related to MD. Only miR-181a has no direct evidence to be involved in the mechanism of MD. In addition to the biological biomarker evidence, the statistical analysis using the large-scale epidemiologic data collected from TWB provides strong evidence on the relationship between MD and migraine. Conclusion: The evidence based on both molecular and epidemiological data reveals the significant association between MD and migraine. This result can help investigate the correlated underlying mechanism of these two diseases.